The highest incidence of cytomegalovirus (CMV*) disease among liver transplant recipients occurs in patients who are seronegative for CMV antibody and receive a liver from a donor who is seropositive for CMV antibody (1). The incidence of CMV disease in this high-risk group of patients is 60-80%. Previous randomized, controlled trials have shown that CMV hyperimmune globulin alone, high-dose oral acyclovir, or sequential prophylaxis with a short course of intravenous ganciclovir followed by oral acyclovir are generally ineffective for prevention of primary CMV disease in CMV-seronegative patients with CMV-seropositive donors (2). In contrast, we observed in a randomized, controlled trial that it is possible to safely eliminate almost all serious CMV disease in liver transplant patients by the administration of prophylactic ganciclovir for the entire 100-day period immediately after transplant (3). Although only 10% of the CMV-seronegative patients with CMV-seropositive donors in this study developed CMV disease, only 10 CMV-seronegative patients with CMV-seropositive donors were studied. Thus, in this report, we provide the results of 100 days of prophylactic ganciclovir in an additional 37 CMV-seronegative patients who received liver grafts from CMV-seropositive donors and were at very high risk for CMV disease. The efficacy of long-term ganciclovir prophylaxis in these 37 patients represents the most effective regimen ever reported in a large number of CMV-seronegative liver transplant recipients with CMV-seropositive donors.
The surgical procedures and posttransplant management used in liver transplant patients at the UCLA Medical Center have previously been published(4, 5). Baseline immunosuppression consisted of either cyclosporine, azathioprine, and corticosteroids or tacrolimus plus corticosteroids. Acute rejection documented by liver biopsy was treated with boluses of intravenous corticosteroids. Episodes of rejection refractory to corticosteroids were treated with OKT3 (Orthoclone; Ortho Biotech, Raritan, NJ).
The regimen of long-term ganciclovir prophylaxis has been previously reported (3). Intravenous ganciclovir was given at a dose of 6 mg/kg once a day through a central venous catheter starting on the first posttransplant day and continuing until day 30 after transplant. From day 31 to day 100 after transplant, the intravenous ganciclovir was given at a dose of 6 mg/kg once per day, Monday through Friday. The dose of ganciclovir was adjusted in patients with renal failure. For patients who developed neutropenia (absolute neutrophil count <109/L) while receiving ganciclovir, prophylaxis was temporarily discontinued and then restarted when the neutrophil count recovered (absolute neutrophil count>109/L).
The CMV serologic status of patients and liver donors was determined before transplantation by latex agglutination (CMV SCAN; Becton Dickinson, Cockeysville, MD). If a clinical syndrome developed in a patient after transplant suggestive of CMV disease, multiple viral cultures of buffy coat, urine, and throat were obtained and serial serologic studies for CMV IgM and IgG antibodies were performed by ELISA (CMV IgM ELISA and CMV IgG ELISA; Kabi Pharmacia Diagnostics, Piscataway, NJ). Whenever indicated by clinical findings, viral cultures of biopsies and bronchoalveolar lavage were also done. Tissue cultures were initially screened for viral antigen by immunofluorescence using monoclonal antibodies to viral proteins and then observed for 4 weeks to detect characteristic cytopathic effects. Biopsy material and bronchoalveolar lavage were examined histologically for typical viral inclusions and then stained immunohistochemically by indirect immunofluorescence using murine monoclonal antibodies to early and late CMV proteins. CMV disease of the liver or gastrointestinal tract was diagnosed by finding histological or culture evidence of CMV in a biopsy sample of the liver or gastrointestinal tract in a patient with liver dysfunction or gastrointestinal symptoms not explainable by other causes. Similarly, CMV pneumonia was diagnosed by demonstrating the presence of CMV in a bronchoalveolar lavage or lung tissue sample in a patient with tachypnea, hypoxemia, fever, and intestinal pulmonary infiltrates not explainable by other obvious causes. CMV syndrome was defined as persistent fever and wasting, with or without leukopenia and thrombocytopenia, which could not be attributed to other causes in a patient with culture or serologic evidence of CMV infection.
Between January 1, 1994, and July 31, 1996, 47 CMV-seronegative patients received liver grafts from CMV-seropositive donors. However, due to the primary physician's decision or administrative error, 10 patients received only short-term prophylactic ganciclovir for less than 7 weeks (mean duration, 3 weeks). The characteristics of these 10 patients and the other 37 patients who did receive long-term ganciclovir prophylaxis for 100 days after transplant are summarized in Table 1. The two groups of patients were similar in terms of age, sex, underlying liver disease, United Network for Organ Sharing status, number of transplants, baseline immunosuppression, and treatment for rejection. The mean age (27 years) of the patients receiving prophylactic ganciclovir for less than 7 weeks was less than the mean age (38 years) of the patients receiving 100 days of prophylactic ganciclovir, but this difference was not significant(p=0.17).
None of the 37 patients given long-term ganciclovir prophylaxis developed CMV disease while receiving the 100 days of prophylactic ganciclovir. However, two patients (5.4%) subsequently developed CMV disease 21 and 88 days, respectively, after the prophylactic ganciclovir was discontinued. Both patients had CMV hepatitis which improved after 2 weeks of ganciclovir therapy. In contrast, 4 of the 10 CMV-seronegative patients (40%) who received liver grafts from CMV-seropositive donors but were given prophylactic ganciclovir for less than 7 weeks (mean duration, 3 weeks) developed CMV disease. Each of these four patients had CMV hepatitis documented by liver biopsy. All four cases improved after 2 weeks of ganciclovir therapy.
The long-term ganciclovir prophylaxis was well tolerated. Only three patients (8.1%) required temporary interruption of the prophylactic ganciclovir for reversible neutropenia. There were no complications associated with the central venous catheters used to administer the ganciclovir.
The mean time of follow-up for all patients is 15 months (range, 5-38 months). Thirty-three of the 37 patients (89%) given long-term ganciclovir prophylaxis are alive. There were no deaths related to CMV disease. The causes of death were multiorgan failure in two cases, recurrent hepatocellular carcinoma in one case, and a multiorgan posttransplant lymphoproliferative disorder in one case. The posttransplant lymphoproliferative disorder occurred in an 11-year-old female patient 7 months after her transplant and 4 months after completion of her prophylactic ganciclovir. Nine of the 10 patients(90%) who received less than 7 weeks of prophylactic ganciclovir are alive.
Although this was not a randomized, controlled study, these results in a larger number of patients reaffirm our previous observations in a controlled, randomized trial comparing long-term administration of ganciclovir with high-dose acyclovir for the prevention of CMV disease in liver transplant recipients (3). In that trial, only 10% of the CMV-seronegative patients with CMV-seropositive donors developed CMV disease when receiving prophylactic ganciclovir for 100 days after transplant. Knowing these results, we had ethical concerns about doing a second randomized, controlled trial in these high-risk patients who have a 60-80% incidence of CMV disease without any antiviral prophylaxis (1).
Our results with long-term ganciclovir prophylaxis in CMV-seronegative patients with CMV-seropositive donors are clearly better than those obtained with CMV hyperimmune globulin, acyclovir, or short courses of ganciclovir. In two randomized, controlled trials evaluating prophylactic CMV hyperimmune globulin in CMV-seronegative liver transplant patients with CMV-seropositive donors, the incidence of CMV disease was 27% and 53%, respectively(6, 7). Similarly, the incidence of CMV disease in CMV-seronegative liver transplant recipients with CMV-seropositive donors and receiving either 3 months of high-dose oral acyclovir or 2 weeks of intravenous ganciclovir followed by 10 weeks of high-dose oral acyclovir was 64% and 43%, respectively (8).
Another approach for decreasing CMV disease after transplantation is preemptive therapy with ganciclovir. Preemptive therapy is designed to limit prophylaxis to patients at greatest risk for CMV disease and thereby to lessen toxicity and cost. High-risk patients include asymptomatic patients who are found to be excreting CMV by culture, polymerase chain reaction, or antigenemia tests and patients who are receiving antilymphocyte antibody therapy for rejection (1). In the high-risk group of CMV-seronegative patients with CMV-seropositive donors, as many as 60% of patients develop CMV disease without any prior positive surveillance culture(9, 10). Similarly, CMV disease still developed in 25-33% of the CMV-seronegative liver transplant patients with CMV-seropositive donors despite frequent surveillance with more sensitive polymerase chain reaction and antigenemia tests (9, 10). Patient availability for frequent monitoring and the relatively high cost of some polymerase chain reaction and antigenemia tests are other potential limitations of preemptive therapy. The administration of preemptive ganciclovir to patients receiving antilymphocyte antibody therapy for rejection is effective in CMV-seropositive transplant recipients but unproven in CMV-seronegative patients with CMV-seropositive donors(2, 11).
Two concerns about long-term ganciclovir prophylaxis are the emergence of resistant organisms and cost. Careful susceptibility studies of CMV isolates from solid organs and bone marrow transplant recipients with CMV infection after antiviral prophylaxis revealed that neither prophylactic acyclovir nor prophylactic ganciclovir selects for ganciclovir-resistant isolates of CMV(12, 13). This low incidence of ganciclovir resistance among transplant recipients, as compared with the higher incidence among HIV-infected patients, may be related to a lower level of viral infection, a lesser degree of immunosuppression, and a shorter period of drug administration in transplant recipients. Most of the cost associated with intravenous ganciclovir prophylaxis is due to the intravenous administration of the drug rather than the drug itself. In a recent double-blind, placebo-controlled trial of oral ganciclovir prophylaxis given to liver transplant recipients for 14 weeks after transplant, CMV disease occurred in 44% of placebo patients but in only 14% of ganciclovir patients who were CMV-seronegative with CMV-seropositive donors (14). Thus, oral ganciclovir may be a cost-effective alternative to intravenous ganciclovir for long-term CMV prophylaxis. We are currently performing a randomized trial comparing oral ganciclovir with intravenous ganciclovir for the prevention of primary CMV disease in CMV-seronegative patients with CMV-seropositive donors.
Acknowledgments. The authors thank Anita Pakrasi, R.N., and Barbara Nuesse, R.N., B.S.N., C.C.T.C., C.P.T.C., for assistance in data collection.
Footnotes
This study was supported in part by the Joanne Barr Foundation and the Dumont Foundation.
Abbreviation: CMV, cytomegalovirus.
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